Caffeine is the most widely consumed behaviorally active drug in the world. Because it has the principal features usually associated with a drug of abuse, caffeine can be a convenient model drug for studying the behavioral and cellular mechanisms of drug reinforcement and related phenomena, such a tolerance and physical dependence. The broad objectives of this project have been to define and quantify effects of acute and chronic treatment wit caffeine at the behavioral and cellular levels. The following specific aim represent a continuation of established lines of investigation as well as new research approaches suggested by recent findings. 1) To test the hypothesis that some behavioral effects of caffeine are due to enhanced postsynaptic dopaminergic mechanism resulting from blockade of adenosine receptors; continuous blockade of adenosine receptors results in a compensatory desensitization of those dopaminergic mechanism and caffeine tolerance. This hypothesis will be tested in rats using the behavioral measures of locomotor activity and unilateral rotation and by in vitro and in vivo measures of postsynaptic dopamine receptor function. 2) To continu to characterize pharmacologically in rats the qualitative differences between the discriminative effects of low and high doses of caffeine and th ability of caffeine to elevate the reinforcement threshold for intracranial self-stimulation. Experiments will be directed at determining the neurochemical bases of those effects and their relevancy to the positive an negative mood states induced by caffeine in humans. 3) To test the hypothesis that caffeine has potent and previously uncharacterized effects on cyclic AMP metabolism and intracellular Ca2+ stores, that these effects are not mediated by blockade of cell-surface adenosine receptors, and that tolerance develops to these effects. Experiments will be performed on a model cell line of CNS origin, the NG108-15 neuroblastome x glioma hybrid cell line, in order to define more clearly these cellular effects of caffeine. Despite the fact that caffeine usually is consumed on a chronic daily basis, there have been relatively few studies of the behavioral and neurochemical consequences of chronic treatment with caffeine. Basic information obtained on the acute and chronic behavioral and cellular actions of caffeine should have broad applicability to many types of drugs of abuse.